Demand for marijuana treatment has far outpaced the development of treatment strategies. Our human laboratory studies have shown that medications may: decrease marijuana withdrawal symptoms and relapse (lofexidine and dronabinol), not affect either outcome (baclofen, mirtazapine), or increase marijuana craving and relapse (quetiapine). Further, cigarette smokers (54% of sample) were 9.5 times more likely to relapse to marijuana than nonsmokers. This proposal will assess how cigarette smoking and medications influence marijuana withdrawal and relapse, with the aim of using these data to improve marijuana treatment outcome. Aim #1: Compare marijuana withdrawal and relapse when marijuana smokers are currently smoking cigarettes and after they have quit. Tobacco-dependent, daily marijuana smokers will be tested in our inpatient model of marijuana relapse during both a Quit and a Smoking-as-Usual condition. We hypothesize that cigarette smoking directly increases the likelihood of marijuana relapse, so that marijuana smokers will relapse less frequently in the Quit than in the Smoking-as-Usual phase. If quitting cigarettes decreases marijuana relapse, there would be a strong rationale for incorporating smoking cessation into marijuana treatment to improve outcome. If tobacco cessation has no effect on relapse, then future studies could focus on developing intensive marijuana treatment strategies for this more intractable subset of marijuana smokers. Aim #2: Determine if the nicotinic acetylcholine receptor (nAChR) partial agonist, varenicline, alone and in combination with the cannabinoid agonist, dronabinol, decreases marijuana withdrawal and relapse. Tobacco- dependent, marijuana smokers will quit smoking cigarettes (using contingency management) and be randomized to receive Placebo or Varenicline. While inpatient, both the Placebo and the Varenicline group will be given active and inactive dronabinol in counter-balanced order. We hypothesize that varenicline combined with a cannabinoid agonist will most efficaciously decrease marijuana relapse in this population. Exploratory Aim #3: To assess stress-responsivity and targeted genetic polymorphisms as predictors of relapse and marijuana effects All participants will contribute a DNA sample and undergo the Trier Social Stress Test (TSST). We predict that: (1) individuals who show a large response (cortisol, heart rate) to the TSST will be more likely to relapse to marijuana, and (2) specific genetic polymorphisms will predict enhanced marijuana intoxication, craving and relapse. The outcome of these studies may be used to better target treatment for vulnerable subtypes of marijuana smokers. Impact: Because most daily marijuana smokers smoke tobacco cigarettes, and because cigarette smoking is predictive of marijuana relapse, this proposal will contribute to marijuana treatment outcome by targeting this intractable and sizable population of marijuana smokers.